It has been known for some time that the vasorelaxant effect of the nitrovasodilators, endothelium-derived relaxing factor (EDRF) and atrial natriuretic peptides is caused by stimulation of guanylate cyclase and an elevation in intracellular cGMP levels in vascular smooth muscle cells. In particular, the effects of 8-azapurin-6-one compounds on vascular smooth muscle have been investigated. For example, the effect of four different nitrovasodilators on cGMP levels and relaxation of bovine coronary artery tissue in the presence of 2-o-propoxyphenyl-8-azapurin-6-one has been investigated [W. R. Kukovetz et al, Naunyn-Schmiedeberg's Arch. Pharmacol., 310, 129-138 (1979)]. In an investigation of the vasorelaxant effects of endothelium derived relaxing factor (ERDF) on rat and rabbit aorta, it was found that 2-o-propoxyphenyl-8-azapurine-6-one potentiated the effects of spontaneously released EDRF [W. Martin et al, J.P.E.T., 237(2), 539-547 (1986)]. The potentiation of atriopeptin-II-induced relaxation of rabbit aorta by 2-o-propoxyphenyl-8-azapurine-6-one has been confirmed [W. Martin et al, Br. J. Pharm., 89, 557-561 (1986)]. In subsequent tests, however, involving an infusion of rat with atriopeptin II, it was found that blood pressure lowering was due to a drop in cardiac output and not due to arterial vasodilation. [R. W. Lappe et al, Circ. Res., 56, 606-612 (1985)]. Thus, in vitro determinations of vasorelaxant activity are not predictive of blood pressure lowering activity in mammals. The inhibitory effects of a class of dibenzoquinazoline diones on cGMP phosphodiesterase from bovine renal artery have been investigated. In this study, it was shown that these compounds lowered blood pressure when injected into spontaneously hypertensive rats. [R. F. G. Booth et al, Biochem. Pharm., 36 (20), 3517-3521 (1987)].
The compound 2-o-propoxyphenyl-8-azapurin-6-one) has been shown to inhibit allergen-stimulated histamine release from mast cells and was initially developed as an orally active prophylactic agent for the treatment of asthma [N. Frossard et al, Br. J. Pharm., 73, 933-938 (1981)]. The mechanism of the mast cell stabilizing effect of this compound is believed to be inhibition of cGMP phosphodiesterase, the enzyme responsible for the metabolism of cGMP, and a subsequent increase in intracellular cGMP levels in mast cells [N. Frossard et al, Br. J. Pharm., 73, 933-938 (1981); R. M. Rudd, Br. J. Dis. Chest., 77, 78-86 (1983)]. U.S. Pat. No. 3,819,631 describes a class of 8-azapurin-6-one compounds, including specifically the compound 2-o-propoxyphenyl-8-azapurin-6-one for use in the treatment of asthma.
Other uses for the compound 2-o-propoxyphenyl-8-azapurin-6-one have been investigated. For example, the antiviral activity of this compound was examined along with other fused pyrimidines [J. E. McCormick et al, Proc. R. Ir. Acad., Sect. B, 83, B(1-16), 125-138 (1983)].